The amelogenin proteins comprise 90% of the organic component of developing enamel matrix, and these proteins are highly conserved evolutionarily. In order to better understand amelogenin function, we have made a mouse model with a targeted disruption of the amelogenin locus, and this is the first knockout mouse described for a tooth extracellular matrix protein. Null mice have hypoplastic enamel with disorganized prism structure. The amelogenin null female mice can be mated with males that contain various amelogenin expression vectors, and male offspring of this mating will express only the transgene, without having any endogenous amelogenin expression. The model system provides a means to screen the significance of mutations in the amelogenin gene, and for function of amelogenins expressed from alternatively spliced mRNAs. This systematic study avoids the complication of Y-chromosomal amelogenin expression, as the sole murine amelogenin gene is on the X chromosome. The aims are (1) to complete the characterization of the amelogenin null dentition for composition and physical characteristics; (2) to create transgenic mice that express single normal or mutated amelogenin proteins, mate them with the null mice, and analyze teeth of offspring; (3) to evaluate LRAP for signal function in vivo and in vitro; and (4) to ascertain additional consequences of absence of amelogenin in maturative ameloblasts, in reparative dentin and during accelerated eruption